EP2041169B1 - Insuline glargine amidifiée - Google Patents

Insuline glargine amidifiée Download PDF

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Publication number
EP2041169B1
EP2041169B1 EP07785902A EP07785902A EP2041169B1 EP 2041169 B1 EP2041169 B1 EP 2041169B1 EP 07785902 A EP07785902 A EP 07785902A EP 07785902 A EP07785902 A EP 07785902A EP 2041169 B1 EP2041169 B1 EP 2041169B1
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EP
European Patent Office
Prior art keywords
insulin
arg
gly
amide
insulin glargine
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Not-in-force
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EP07785902A
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German (de)
English (en)
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EP2041169A1 (fr
Inventor
Paul Habermann
Frank Zocher
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Sanofi Aventis Deutschland GmbH
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Sanofi Aventis Deutschland GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/62—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to the amidation-modified insulin glargine Gly (A21), Arg (B31), Arg -amide (B32) human insulin (insulin glargine amide).
  • type II diabetes is not generally deficient in insulin, but in a large number of cases, especially in advanced stages, treatment with insulin, possibly in combination with an oral antidiabetic agent, is the most favorable form of therapy considered.
  • insulin release by the beta cells of the pancreas is strictly coupled to the concentration of blood glucose.
  • Increased blood glucose levels as they occur after meals, are rapidly compensated by a corresponding increase in insulin secretion.
  • the plasma insulin level drops to a basal level sufficient to ensure a continuous supply of insulin-sensitive organs and tissues with glucose and to keep hepatic glucose production low at night.
  • the replacement of the body's insulin secretion by exogenous, usually subcutaneous administration of insulin generally does not reach the quality of the physiological regulation of blood glucose described above. Often there are derailments of blood glucose, as diabetics misjudge the situation. In addition, however, increased blood glucose levels without initial symptoms represent a significant health risk over years.
  • Diabetic late damage is micro- and macrovascular damage, which may be u. May manifest as retinopathy, nephropathy, or neuropathy and lead to blindness, renal failure, and loss of extremities, as well as being associated with an increased risk of cardiovascular disease. From this it can be deduced that an improved therapy of diabetes must primarily aim to keep the blood glucose as close as possible to the physiological range.
  • Insulin is a 51 amino acid polypeptide distributed among 2 amino acid chains: the 21 amino acid A chain and the 30 amino acid B chain. The chains are linked by 2 disulfide bridges. Insulin preparations have been used for diabetes therapy for many years. Not only naturally occurring insulins are used, but more recently also insulin derivatives and analogues.
  • Insulin analogs are analogs of naturally occurring insulins, namely human insulin or animal insulins, which differ in substitution of at least one naturally occurring amino acid residue with other amino acid residues and / or addition / removal of at least one amino acid residue from the corresponding otherwise identical naturally occurring insulin.
  • US 5,656,722 z For example, insulin describes glargine (Arg (B31), Arg (B32), Gly (A21) human insulin). The added and / or replaced amino acid residues may also be those that are not naturally occurring.
  • Insulin derivatives are derivatives of naturally occurring insulins or insulin analogues in which one or more amino acid residues and / or the N or C termini of the A and / or B chain are substituted by functional groups.
  • the functional groups are selected from a group containing amide radicals, amine radicals, carboxy radicals, alkyl radicals, alcohol radicals and alkoxy radicals.
  • Effective insulin therapy makes use of so-called basal insulins. These are formulations which enable a slow, continuous release of exogenously applied insulin. As a result, a basal insulin concentration in the body is achieved for a long time, which has an advantageous effect on the physiological condition of the person suffering from diabetes. Ideally, the insulin action is delayed and as shallow as possible, so that the risk of short-term hypoglycaemia is clearly minimized and the application can be carried out without prior ingestion of food.
  • the recombinant insulin analog Arg (B31), Arg (B32), Gly (A21) human insulin is characterized by the fact that in many patients it only needs to be supplied to the body every 24 hours - ie only once a day - in order to achieve a basal effect. It comes to an improved blood sugar control, for example, leads to a reduction of Hba1c value.
  • insulin glarginamide which is produced by amidation of arginine in position B32 of insulin glargine, has a significantly flatter and thus more advantageous time / effect profile than insulin glargine itself.
  • the blood sugar value drops without a clear nadir
  • Insulin glargine amide thus has a surprisingly advantageous quality in the pharmacological sense. The risk of hypoglycaemia during administration is thus minimized.
  • Applying lantusamide results in a normal fasting blood glucose level of 70-110 mg / dl glucose.
  • insulin glarginamide surprisingly has an extended effect on insulin glargine. Insulin glargine amide is thus the subject of the invention.
  • the insulin glarginamide is the subject of a pharmaceutical formulation.
  • a pharmaceutical one Mixture which unfolds after application advantageously in the best way the effect of insulin glargine amide. It is based on aqueous solutions. Accordingly, further components must be miscible. It is advantageous that the preparation should not contain components derived from animal sources. This minimizes the risk of viral contamination. It is also advantageous to prevent microbial contamination by adding preservatives. By adding isotonic agents, a possible negative effect of the formulation on the physiology of the tissue cells at the site of application can be compensated.
  • protamine can have a stabilizing effect, so that largely salt-free insulin preparation can be obtained if protamine is added to the formulation.
  • the addition of a phenolic component can stabilize the hexameric structure of the insulin analog and thus promote the delay effect on onset of action.
  • the glargine amide may be parallel to fast-acting insulins such as Apidra ®, NovoRapid ®, Humalog ® or under development insulin derivatives or formulations with appropriate time - are added / action profile. It is clear to the person skilled in the art that correspondingly formulated mixtures of the respective insulin components can be used for this purpose.
  • the amide can be taken also preferred by individuals also who use inhalable insulin Exubera ® as.
  • glarginamide can be used in pharmaceutical preparations containing peptides described by activity comparable to GLP-1 (glucagon like peptides -1).
  • peptides examples include GLP-1 (7-37), Exenatide (Byetta ®) or peptides, their preparation in patent applications WO 2006/058620 .
  • WO 2001/04156 and WO 2004/005342 describe, dar.
  • the yield can be positively influenced by varying the reaction conditions.
  • This is familiar to the person skilled in the art and also the subject of the invention.
  • plasmids pB40 and pINT91d are described which allow the expression of minipro insulin as part of a fusion protein.
  • Arg (B31) By replacing asparagine in position 21 of the insulin A chain with glycine, Arg (B31), Gly (A21) miniprosulin can be directly prepared from these fusion proteins, which, after tryptic digestion, can be converted directly into the precursor for the production of insulin glargine amide , Corresponding fusion proteins do not necessarily have to be produced intracellularly.
  • this proinsulin analog can also be prepared by bacterial expression with subsequent secretion into the periplasm and / or into the culture supernatant.
  • the European patent application EP-A 1 364 029 describes this by way of example.
  • the use of Arg (B31), Gly (A21) human insulin precursors, which arise directly after expression from such bacterial processes, is also the subject of the invention.
  • Insulin glargine in which the C-terminal carboxyl group is amidated, is referred to as insulin glargine amide.
  • the present invention thus relates to amidated insulin glargine of the form Gly (A21), Arg (B31), Arg (B32) -NH 2 human insulin (insulin glargine amide).
  • Another object of the invention is a method for producing an insulin glargine, wherein a precursor of insulin glarginamide of the form Gly (A21), Arg (B31) human insulin is produced recombinantly, a coupling with arginine amide in the presence of an enzyme with trypsin activity is performed, and the insulin glarginamide is isolated.
  • Another object of the invention is the use of insulin glarginamide in a process for the preparation of a medicament for the treatment of diabetes, in particular diabetes type I or type II diabetes.
  • Another object of the invention is a medicament containing insulin glarginamide, which is in particular an aqueous formulation or a powder.
  • the drug is a pharmaceutical preparation, which is preferably a solution or suspension for injection purposes; it is characterized by a content of at least one amidated insulin glargine, in particular insulin glargamide, and / or at least one of its physiologically tolerated salts in dissolved, amorphous and / or crystalline - preferably in dissolved form.
  • the preparation preferably has a pH of between about 2.5 and 8.5, in particular between about 4.0 and 8.5, contains a suitable isotonic agent, a suitable preservative and optionally a suitable buffer, and preferably also a certain zinc ion concentration, all of course in sterile aqueous solution.
  • a suitable isotonic agent e.g., a suitable preservative and optionally a suitable buffer, and preferably also a certain zinc ion concentration, all of course in sterile aqueous solution.
  • the totality of Preparation ingredients except the active ingredient forms the preparation carrier.
  • Suitable isotonic agents are, for example, glycerol, glucose, mannitol, NaCl, calcium or magnesium compounds such as CaCl 2 etc.
  • the choice of the isotonic agent and / or preservative influences the solubility of the amidated insulin glargine or its physiologically tolerated salt at the weakly acidic pH values.
  • Suitable preservatives are e.g. Phenol, m-cresol, benzyl alcohol and / or p-hydroxybenzoic acid ester.
  • buffer substances in particular for the adjustment of a pH value between approximately 4.0 and 8.5, e.g. Sodium acetate, sodium citrate, sodium phosphate, etc. can be used. Otherwise, physiologically harmless dilute acids (typically HCl) or alkalis (typically NaOH) are also suitable for adjusting the pH.
  • HCl physiologically harmless dilute acids
  • NaOH alkalis
  • the preparation has a zinc content, it is preferred to be from 1 ⁇ g / ml to 2 mg / ml, especially from 5 ⁇ g to 200 ⁇ g zinc / ml.
  • Unmodified insulin preferably bovine, porcine or human insulin, in particular human insulin, or insulin analogs and derivatives thereof can also be admixed for the purpose of varying the active substance profile of the preparation according to the invention.
  • one or more exendin-4 derivatives or peptides characterized by GLP-1 (glucagon like peptide-1) -like activity can be mixed.
  • Such drugs (preparations) are also the subject of the invention.
  • Preferred drug concentrations are those corresponding to about 1-1500, more preferably about 5-1000 and especially about 40-400 international units / ml.
  • Fig. 1 Hypoglycemic effect of various insulin analogues in dogs.
  • RR-COOH insulin glargine;
  • RR-NH 2 insulin glarginamide
  • Example 1 Gene sequence for secretion of a hirudin Arg (B31), Gly (A21) insulin fusion protein by baker's yeast
  • EP-A 1 364 032 suggests the use of hirudin as a fusion partner for the expression and secretion of pharmaceutically interesting value proteins in yeasts.
  • Example 1 of the patent application EP-A 1 364 032 describes a host vector system for producing a fusion protein consisting of a hirudin derivative and minipro insulin. This system can be used for the preparation of miniproinsulins leading to the claimed insulin glarginamide as a precursor.
  • Patent application EP-A 1 364 032 by replacing the primer insnco1 rev and thus changing the codon in position A21.
  • the primer completely covers the gene segment coding for the amino acids A15-A21 of the insulin analogue. Combining this primer with the primer SEQ ID NO: 4 of Example 1 of the patent application EP-A 1 364 032 and uses the plasmid pADH2Hir_ins as a 'template', it can be generated via PCR, a DNA fragment that is inserted after digestion with the restriction enzymes Kpnl and Ncol in the corresponding open expression vector and contains the desired fusion protein.
  • the vector is named pADH2Hir_ins_glyA21.
  • the fusion protein is according to Example 3 of the patent application EP-A 1 364 032 expressed and according to Example 6 to Gly (A21) - minipro insulin processed and purified by cation exchange chromatography.
  • the material of the fraction containing minipro insulin is used to prepare Gly (A21), Arg (B31), Arg (B32) -NH 2 human insulin according to Example 5 of the present application.
  • Example 2 Gene sequence for the direct secretion of Gly (A21), Arg (B31), human insulin precursor by baker's yeast
  • DNA of Example 7 of the patent application EP-A 1 364 032 The plasmid pADH2Hir_ins_glyA21 described is used to prepare a vector construct for the direct secretion of Gly (A21), Arg (B31) human insulin.
  • alpha_insf1 5'-TTTTTTGGATCCTTTGGAATAAAAGATTTGTTAACCAACACTTGTGTG-3 '(SEQ ID NO: 2)
  • Gly (A21), Arg (B31) - minipro insulin becomes appropriate EP-A 0 347 781 , Example 9, enriched and purified by trypsin cleavage via cation exchange chromatography. Material of the fraction containing miniprosulin is used to prepare Gly (A21), Arg (B31), Arg (B32) human insulin according to Example 5 of the present application.
  • Example 3 Gene sequence for secretion of a hirudin-Gly (A21), Arg (B31) human insulin fusion protein by Pichia pastoris
  • the primer ins_gly_rev2 which later makes possible the possibility of expressing Gly (A21) human insulin with the PCR product, is used: 5'-TTTTTGGCGCCGAATTCACTACTATTAGCCACAGTAGTTTTCCAGCTGG-3 '(SEQ ID NO.:4)
  • the resulting plasmid is named pPich_Hir_ins-GlyA21.
  • the purification of Gly (A21), Arg (B31) - minipro insulin as starting material is carried out as described.
  • Example 5 Preparation of Gly (A21), Arg (B31), Arg (B32) -NH 2 - human insulin from a Gly (A21), Arg (B31) human insulin precursor via coupling with arginine amide
  • the reaction is stopped by addition of TFA to pH 2.5 and analyzed by HPLC. It forms> 60% Gly (A21), Arg (B31), Arg (B32) human insulin.
  • the amidated analogue (insulin glarginamide) is purified analogously to US 5,656,722 ,
  • Example 6 Gene sequence for the direct secretion of a Lys (B31) precursor by baker's yeast
  • Two primers are synthesized which serve to introduce the sequence Ala (B30), Ala (C1), Lys (C2): a29_a30_k31f 5'-GTTTCTTCTACACTCCAAAGGCGGCTAAAGGTATCGTTGAACAATGTTG-3 '(SEQ ID NO: 7) and a29_a30_k31rev 5'-CAACATTGTT CAACGATACC TTTAGCCGCC TTTGGAGTGT AGAAGAAAC -3 '(SEQ ID NO: 8)
  • the primer alpha_insf1 5'-TTTTTTGGATCCTTTGGAATAAAAGATTTGTTAACCAACACTTGTGTG-3 '(SEQ ID NO: 9) covers the sequence of the C-terminus of the alpha factor, codons for Lys-Arg and the N-terminus of the minipro insulin sequence.
  • DNA of the plasmid pADH2Hir_ins from Example 1 of the application WO 02 / 070722A1 serves as a template for two polymerase chain reactions.
  • reaction 1 the primers a29_a30_k31f and insnco1 rev (SEQ ID NO WO 02 / 070722A1 ) and in reaction 2 the primers a29_a30_k31 re and alpha_insf1 are used.
  • the standard reactions are carried out and the resulting PCR fragments are isolated. Aliquots of the two yields are pooled and serve as templates for a third reaction with the primers insnco1 rev and SEQ ID NO: 6 WO 02 / 070722A1 , The resulting PCR fragment is cloned and expressed as described in Example 8.
  • the insulin precursor is as in DE3844211 reacted with lysyl endopeptidase (LEP) and trypsin and purified (Example 1).
  • LEP lysyl endopeptidase
  • Example 1 The insulin precursor is as in DE3844211 reacted with lysyl endopeptidase (LEP) and trypsin and purified (Example 1).
  • 10 mg of the insulin precursor are dissolved in Tris buffer (pH 8.0) and LEP from Lysobacter enzymogenes added (0.01 ml of a 1 mg / ml conc. Solution in water, Merckbiosciences). It is incubated at room temperature for 2 h and purified by RP-HPLC (Nucleosil 120-5 column).
  • the Gly (A21) B (1-29) - A (1-20) split insulin precursor is modeled after DE3844211 reacted with Thr-Arg (Boc) -Arg (Boc) -NH 2.
  • 10 mg of the desThr insulin precursor are dissolved in 0.25 ml of 10 M acetic acid and 0.7 ml of 1.5 M Thr-Arg (Boc) -Arg (Boc) -NH 2 dissolved in DMSO / 1,3-butanediol (1: 1) are added. It is then 0.15 ml LEP (15 mg / ml, dissolved in water). It is incubated at room temperature for 2 h.
  • the deprotection is carried out by addition of 1 M HCl / acetic acid and incubation at 0 ° C.
  • the hypoglycemic effect is studied in healthy Beagle male dogs. Subcutaneously, a dose of 0.3 IU / kg body weight is administered. In a control group, dogs are treated with the same dose of insulin glargine and another group receives a placebo injection without insulin supplement. During the first 2 hours after injection, the animals are bled every half hour for blood glucose determination, then every hour until the eighth hour. It has been shown that insulin glargine-amide as well as insulin glargine have a delayed time / effect profile, but the profile of the amide is clearly advantageous, since when the onset of action, the blood sugar value drops without a distinct low point (nadir). The result is in FIG. 1 shown.

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Abstract

L'invention concerne une insuline glargine modifiée par amidification, notamment une insuline humaine Gly(A21), Arg(B31), amide d'Arg(B32) (amide d'insuline glargine).

Claims (10)

  1. Insuline humaine Gly(A21), Arg(B31), Arg(B32)-NH2 (insuline glarginamide).
  2. Procédé de préparation d'insuline glarginamide selon la revendication 1.
  3. Procédé selon la revendication 2, pour la préparation d'insuline glarginamide selon la revendication 1, dans lequel on prépare par recombinaison un précurseur de l'insuline glarginamide se présentant sous la forme insuline humaine Gly(A21), Arg (B31), on procède à un couplage avec de l'argininamide en présence d'une enzyme ayant une activité de trypsine, et on isole l'insuline glarginamide.
  4. Utilisation de l'insuline glarginamide selon la revendication 1 dans un procédé de fabrication d'un médicament pour le traitement du diabète.
  5. Procédé selon la revendication 4, dans lequel on utilise l'insuline glarginamide dans un procédé de fabrication d'un médicament pour le traitement du diabète de type I ou de type II.
  6. Médicament contenant de l'insuline glarginamide selon la revendication 1.
  7. Médicament selon la revendication 6, qui se présente sous forme d'une formulation aqueuse.
  8. Médicament selon la revendication 6, qui se présente sous forme d'une poudre.
  9. Médicament selon la revendication 7, dans lequel l'insuline glarginamide est présente sous une forme dissoute, cristalline et/ou amorphe.
  10. Médicament selon la revendication 7, qui contient en outre un ou plusieurs dérivés de l'exendine-4 ou peptides exendine-4, qui sont caractérisés par une activité comparable à celle du GLP-1 (Glucagon like peptide-1).
EP07785902A 2006-07-11 2007-07-05 Insuline glargine amidifiée Not-in-force EP2041169B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006031962A DE102006031962A1 (de) 2006-07-11 2006-07-11 Amidiertes Insulin Glargin
PCT/EP2007/005932 WO2008006496A1 (fr) 2006-07-11 2007-07-05 Insuline glargine amidifiée

Publications (2)

Publication Number Publication Date
EP2041169A1 EP2041169A1 (fr) 2009-04-01
EP2041169B1 true EP2041169B1 (fr) 2011-08-31

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US (1) US8048854B2 (fr)
EP (1) EP2041169B1 (fr)
JP (1) JP5325778B2 (fr)
AR (1) AR061866A1 (fr)
AT (1) ATE522545T1 (fr)
DE (1) DE102006031962A1 (fr)
TW (1) TW200817432A (fr)
WO (1) WO2008006496A1 (fr)

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EP2041169A1 (fr) 2009-04-01
US8048854B2 (en) 2011-11-01
JP5325778B2 (ja) 2013-10-23
ATE522545T1 (de) 2011-09-15
JP2009542741A (ja) 2009-12-03
AR061866A1 (es) 2008-09-24
DE102006031962A1 (de) 2008-01-17
TW200817432A (en) 2008-04-16
WO2008006496A1 (fr) 2008-01-17

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